HK1003054B - Retinoids - Google Patents

Description

The present invention relates to new retinoids of general formula In which XOxo or a residue OR1 in position 4 or 5;R1 is hydrogen, alkyl or acyl; andR2 is hydrogen or alkyl; the dotted bonds are optional and a 3,4-double bond can only be present if X is in position 5; and pharmaceutical salts of carbonic acids of formula I.

The invention also relates to a process for the manufacture of these retinoids and their salts, derivatives or pharmaceutical preparations containing these salts, and the use of these retinoids and their salts as medicinal products or for the manufacture of medicinal products.

Pharmaceutical preparations containing vitamin A derivatives are known, e.g. GB A 2 156 676 describes preparations containing 4-oxo and 4-hydroxy-13-cis vitamin A derivatives for the treatment of acne and seborrhea.

Err1:Expecting ',' delimiter: line 1 column 147 (char 146)

Compounds of formula I in which X is a residue of OR1 may be present as R- or S-enantiomers or as racemates.

A preferred group of compounds of formula I are compounds of formula In particular, those of the formulas where X, R1 and R2 have the above meanings.

Other subgroups of compounds of formula I are the compounds of formula ID, IE, IF and IG Other

Examples of compounds of formula I are: The value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product and the value of all the materials of Chapter 9 used do not exceed 20% of the ex-works price of the product

The compounds of formula I and their salts can be prepared according to the invention by taking a compound of the general formula wherein A is a phenyl or a substituted phenyl and Y- an anion, and X and the dotted lines have the meaning given above, Transformed with 5-hydroxy-4-methyl-5H-furan-2-one in the presence of a base, isomers in the reaction product in which the C=C double bond formed during the reaction has a cis configuration are isomerised to the trans isomer and, if desired, the reaction product of formula I is subjected to one or more of the following operations: (a) esterification of a carboxyl or hydroxy group; (b) etherisation of a hydroxy group; (c) oxidation of a hydroxy group to oxogruppe; (d) reduction of an oxogruppe to hydroxy group; (e) steric inversion of a hydroxy group; and (f) transfer of a carboxy group to a salt.

The above transpositions can be carried out by methods which are known to man.

The implementation of the compound II can be carried out by the known methods of the Wittig reaction, in which the reaction partners are mixed in the presence of an acid-binding agent, e.g. a strong base such as KOH in an aqueous solvent; or sodium hydride, K-tert butylate or sodium ethyllate in an anhydrous solvent such as dimethylformamide or methyl chloride, in a temperature range of about -30°C to room temperature. Preferably, compounds of formula II containing X are oxo or hydroxy. The Wittig reaction produces a mixture of cis/trans isomers that in the reaction is called isomeric double bond C=C. This mixture can be selectively bound by 4E/Z isomeric in a manner similar to P-E4 (see P-E2 isomeric catalysis).

Of the inorganic acid anions, Y- is the chlorine and bromine ion or the hydrosulfate ion, of the organic acid anions, the tosyloxy ion is preferred.

The esterification of a carboxyl group in a compound of formula I can be done, for example, by transformation with an alkyl halogenide in the presence of a base, such as potassium carbonate, in an organic solvent, such as ethyl acetate. The esterification of a hydroxy group can be done by transformation with an acyl halogenide in the presence of a base, such as pyridine. A hydroxy group can be oxidized to the oxygroup by the methods of Swern (dimethyl sulfoxide/oxalyl chloride) or Dess-Martin (periodinan). The reduction of an oxygroup to the hydroxy group can be performed with hydroxy reducing agents such as NaB4H. The configuration of the hydroxy group can be performed after a reaction with azotube triphosphate (methyl methacrylate, methylenedioxyphoribetyl phosphate, and nitroglycerin).

Examples of salts into which the carbonic acids of formula I can be converted are alkali metal salts such as Na and K salts, earth alkali metal salts such as Ca and Mg salts, and animonium salts such as salts with alkylamines and hydroxyalkylamines or with other organic bases such as dimethylamine, diethanolamine and piperidine.

The compounds of formula II can be prepared as described in Pure and Appl.Chem. 57, 741 (1985) or in the additional literature referred to therein.

The compounds of the invention may be used for the treatment and prophylaxis of dermatological conditions associated with epithelial lesions, e.g. acne and psoriasis, as well as malignant and pre-malignant epithelial lesions, tumors and precancerous changes of the mucous membranes of the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.

The compounds of formula I and their salts can therefore be used in the form of pharmaceutical preparations.

For systemic applications, preparations may be prepared, for example, by adding a compound of formula I or a salt thereof as an active ingredient to non-toxic, inert, intrinsically solid or liquid media commonly found in such preparations.

The products may be administered enteral, parenterally or topically. For enteral application, products are suitable in the form of tablets, capsules, dressing, syrups, suspensions, solutions and suppositories. For parenteral application, products are suitable in the form of solutions for infusion or injection.

For enteral and parenteral administration, formula I compounds may be administered in doses of approximately 10 to 400 mg, preferably 20 to 200 mg/ day, to adults.

For topical use, the active substances are used as appropriate in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Preferably, ointments and creams and solutions. These preparations for topical use can be prepared by spraying the process products as an active ingredient on non-toxic, inert, topical-treatment-appropriate solid or liquid media, which are inherently common in such preparations.

For topical application, solutions of 0.1 to 5% and preferably 0.3% to 2% and ointments or creams of 0.1 to 5% and preferably 0.3% to 2% are suitable.

The preparations may be mixed with an antioxidant, e.g. tocopherol, N-methyl-g-tocopheramine and butyl hydroxyanisol or butyl hydroxytoluol.

The efficacy of the compounds of the invention in the treatment of acne can be demonstrated by the experimental arrangements described below: Inhibition of proliferation of human sebocytes (in vitro): Methods in enzymology 190, 334 (1990), T. Doran and S. Shapiro2. The resulting phenotype can no longer produce sebum. The measurement of keratin 7 induction is based on an ELISA assay using a mouse monoclonal antikeratin 7 antibody. The following table shows the results of the analysis: The skin of the mini-pig has a similar anatomical structure to human skin. In particular, the sebum glands are similar to those of human acne patients. Under retinoid treatment, they show the same histological changes as in humans. The pigs receive a daily oral dose of the test substance for 8 weeks. Every 2 weeks a biopsy is taken and histologically examined. Other

The compound produced in example 1 shows in this study a significant reduction in the size of the sebaceous glands after 3-4 weeks at a dose of 10 mg/kg, which has largely disappeared after 8 weeks.

Teratogenic effects are among the most unnoticed side effects of all retinoids. The compounds claimed here are significantly less teratogenic than, for example, isotretinoin or tretinoin. To evaluate the teratogenic potential, the limb bud cell culture assay was used (Literature: Arch. Toxiol. 60, 403 [1987] A. Kistler). Other

Verbindung von Beispiel
1	>1000
3	>1000
4	>1000
Isotretinoin	200
Tretinoin	80

The invention is further explained by the following examples.

Example 1

50 g [(2E,4E) - ((R) -5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl) -3-methyl-2,4-pentadienyl]triphenylphosphonium chloride were dissolved in 500 ml of isopropanol and mixed with 11 g 5-hydroxy-4,5-methyl-5H-furan-2-one. After cooling the mixture to -30°C, 120 ml of aqueous 2N KOH solution were added and stirred for another hour at -30°C under argon. The reaction mixture was then whisked into 1.3 l of ice water, extracted 6 times with 500 ml of an alkaline hexane/esterified mixture (2:1) each, which was dissolved in an organic solution by extraction of 800 ml of coal-based ice oxide. The solution was dissolved in 3 ml of sulphuric acid, extracted with 3 ml of organic solvent, and dissolved in a solution of 0.0 ml of sulphuric acid.The resulting yellow crystalline raw product was mixed with 500 ml of acetonitrile and heated to 50°C under argon. A clear yellow solution was obtained by portionally adding about 700 ml of acetonitrile. After adding 1.1 g of triphenylphosphine and 118 ml of a 0.125% solution of palladium (II) nitrate to acetonite, the reaction medium was stirred for 3 hours at 50°C. The final product crystallized when the reaction solution was cooled to -10°C. It was deep-fried, washed with hexanum rock and converted to hexanum at 40°C (2 °C/ 15 °C) at vacuum (2 °C/ 15 °C).The following substances are to be classified in the same group as the active substance: $\frac{\text{20}}{\text{D}}$ The concentration of dioxin in the solution is -49.7 (c=1, dioxan).

Example 2

3 g of the carbonic acid obtained in accordance with example 1 were successively added to 120 ml of methylethylketone, 5.2 g of finely ground potassium carbonate and 7.4 g of ethyl iodide and heated with argon and strong stirring for 2.5 hours at the return flow. The reaction mixture was poured on ice/1N hydrochloric acid, extracted with ether, washed with water, dried and evaporated. The crude oil product was filtered with a silica gel (lubricant Hexan/Essigester 2:1) and decrystallized from HexanE. 2.9 g (2Z,4E,6E,8) -R) -94-hydroxy-2,6-trimethylhexyl-1,3-6,6-trimethylhexyl-3,7-nona-methyl-2,6-dimethyl-acetyl-acetyl-acetyl, S4,-methacrylate, obtained in crystalline salts, 93°C, [5-9,5] $\frac{\text{20}}{\text{D}}$ The concentration of dioxins in the solution is -45.5.

Example 3

In analogy to example 1, the conversion of 10 g [(E) - ((R) -)) 5- ((4-Hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl) -3-methyl-2-penten-4-ynyl]triphenylphosphonium chloride with 2,3 g 5-Hydroxy-4-methyl-5H-furan-2-one after palladium catalyzed isomerization of the raw product and recrystallization from hexane/esisi ester 3,1 g (2,4E,6E) - ((R) -9) 4-(Hydroxy-2,6,6-trimethyl-cyclohexen-1-yl) -3-dimethyl-2,4,6-trien-8-nona-acetic acid was obtained as yellow crystals, S.mp-189-190°C. (Zersers) [α] $\frac{\text{20}}{\text{D}}$ The solution is to be used in the manufacture of the product.

Example 4

After cooling the reaction mixture to -30°C, 20 ml of aqueous 2N potassium hydroxide solution were added. After 30 minutes of agitation at -30°C, the reaction mixture was dissolved in ice water, after 3 hours of hexane extraction, the alkaline crystalline phase was dissolved in ice water, after 3 hours of hexane extraction, the alkaline crystalline phase was dissolved in ice water, after 3N sulphuric acid extraction, and after 50-3,3 times the organic crystalline phase was dissolved in organic crystalline phase. The solution was dissolved in water, after dissolving in water, in 0.3-0.5-0.5-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.4-0.

Example 5

After cooling the reaction mixture to -30°C, a solution of 1.76 g of potassium hydroxide was added to 30 ml of isopropanol. After 40 minutes of stirring at -30°C, the reaction mixture was dissolved in 200 ml of ice water, extracted 6 times with a hexane/ dimethyl-5H-furan-2-one crystalline phase, dissolved in 100 ml of isopropanol, extracted from the organic phase with a tropical acid crystalline phase, extracted from a dimethyl-3H-crystalline phase. The solution was dissolved in water of 0.07-0.07-0.07-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.06-0.07-0.07-0.06-0.07-0.07-0.06-0.07-0.06-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-0.07-

Example 6

0,5 g (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-5-oxo-cyclohex-1-enyl) -nona-2,4,6,8-tetrahydric acid were dissolved in 25 ml of ethanol at low heat and refrigerated with 100 mg of sodium borohydride. After stirring for 1 hour at 0°C, the reaction mixture was poured on ice water, acidified with 2N hydrochloric acid and extracted with acetic acid. The organic phases were washed (H2O), dried (NaSO 15224), and evaporated. The amorphous residue was filtered over a small column (silicon, hexan/esterium = 1:1) and hexan/esterium was obtained.

Example 7

After 2 hours of stirring at room temperature, the residue was evaporated, taken up with ether and kept in the refrigerator for 3 hours. The resulting nitrous oxide (triphenylphosphorus) was separated, the nitrous oxide was isolated and purified by hydrochloric acid crystallography (silicon tetrahydroxy, hexane/esters 5), resulting in 0,68 g of nitrous oxide, which was dissolved in 15 ml of nitrous oxide. The resulting nitrous oxide (Ethylphosphorus) was dissolved in water (Ethylsodium) for a period of 1,5 to 4,8 mg (Ethylsodium) and dissolved in water (Ethylsodium) for a period of 1,5 to 4,8 hours (2,8 to 4,8 mg/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol/mol $\frac{\text{20}}{\text{D}}$ The maximum concentration of the active substance is calculated as follows:

Example 8

1 g of the carbonic acid produced in accordance with example 4 was suspended in 50 ml of methylethylketone, mixed with 1,5 g of finely ground potassium carbonate and 1,3 ml of ethyl iodide and heated at the return flow for 1 hour. The cooled reaction mixture was poured on ice water, neutralized with 1 N of hydrochloric acid, extracted with acetic acid, washed (H2O), dried (Na2SO4) and evaporated. The resulting yellow oil was purified by chromatography (silicon gel, hexan/acetic acid = 2:1) to yield 1,5 g of the corresponding ethyl ester as yellow oil.

1,18 g of Certrichloride·7H2O were dissolved in 25 ml of methanol and mixed successively with a solution of the above ethyl ester in 5 ml of methanol and 120 mg of sodium borohydride. After the gas evolution had subsided (about 5 minutes), the orange residue was evaporated and cleaned by chromatography (silica gel, hexane/acetic acid =4.8:1). 1,04 g of the corresponding hydroxy ester was obtained as yellow oil. This oil was dissolved in 25 ml of ethanol, mixed with a solution of 1,6 g of ethyl ester in 12 ml of water and stirred for 4 hours at 40 °C under argon. The crystallised reaction column was crystallised in ice water, heated to pH 1N-3 with acetic acid, and then extracted with an ammonium oxide solution (E6,6-92-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-OH, 2-

Example A

The hard gelatin capsules can be prepared as follows: Other

Bestandteile	mg/Kapsel
1. sprühgetrocknetes Pulver enthaltend 75% Verbindung I	20
2. Natriumdioctylsulfosuccinat	0,2
3. Natriumcarboxymethylcellulose	4,8
4. mikrokristalline Cellulose	86,0
5. Talk	8,0
6. Magnesiumstearat	1,0

The spray-dried powder based on the active substance, gelatine and microcrystalline cellulose, with a mean grain size of < 1 μm (measured by autocorrelation spectroscopy), is moistened and kneaded with an aqueous solution of sodium carboxymethyl cellulose and sodium diodiocyl sulphosuccinate. The resulting mass is granulated, dried and sieved, and the resulting granulate is mixed with microcrystalline cellulose, talc and magnesium stearate. The powder is filled in capsules of size 0.

Example B

The tablets can be made as follows: Other

Bestandteile	mg/Tablette
1. Verbindung I als feingemahlenes Pulver	20
2. Milchzucker pulv.	100
3. Maisstärke weiss	60
4. Povidone K30	8
5. Maisstärke weiss	112
6. Talk
7. Magnesiumstearat	4

The fine powder is mixed with milk sugar and some of the cornstarch, moistened and kneaded with an aqueous solution of Povidone K30, and the resulting mass is granulated, dried and sieved, the granules are mixed with the remaining cornstarch, talc and magnesium stearate and pressed into tablets of appropriate size.

Example C

A lotion can be made as follows: Other

Bestandteile
1. Verbindung I, feingemahlen	1,0 g
2. Carbopol 934	0,6 g
3. Natriumhydroxid	q.s. ad pH 6
4. Aethanol, 94%	50,0 g
5. entmineralisiertes Wasser	ad 100,0 g

The active substance is incorporated into the mixture of ethanol, 94%ig/water, under protection from light, the carbopol 934 is stirred until complete gelatinization and the pH is adjusted with sodium hydroxide.

Example D

A cream can be made from the following ingredients in a known way: Other

	Gew.-%
Verbindung der Formel I	0,1-5
Cetylalkohol	5,25-8,75
Arlacel 165 (Glyceryl/PEG 100-stearat)	3,75-6,25
Miglyol 818 (Capryl-/Caprin-/Linolsäure triglycerid)	11,25-18,75
Sorbit-Lösung	3,75-6,25
	0,075-0,125
Carbopol 934P (Carbomer 934P)	0,15-0,25
butyliertes Hydroxyanisol	0,0375-0,0625
Methylparaben	0,135-0,225
Propylparaben	0,0375-0,0625
NaOH (10% solution)	0,15-0,25
Wasser q.s.	100,00

Example E

A gel can be made from the following ingredients in a known way: Other

	Gew.-%
Verbindung der Formel I	0,1-5
Pluronic L 101 (Poloxamer 331)	10,00
Aerosil 200 (Siliciumdioxid)	8,00
PCL Liquid (Fettsäureester	15,00
Cetiol V (Decyloleat)	20,00
Neobee Oil (Triglycerid mittlerer Kettenlänge)	15,00
Euhanol G (Octyldodecanol), q.s.	100,00

The physical properties of the preparations may be altered by varying the ratios of the examples D and E excipients.

Claims (19)

1. Compounds of the general formula wherein

   X   is oxo or a residue OR¹ in the 4- or 5-position;

   R¹   is hydrogen, alkyl or acyl; and

   R²   is hydrogen or alkyl;

   the dotted bonds are optional and a 3,4-double bond can be present only when X is in the 5-position; as well as pharmaceutically usable salts of carboxylic acids of formula I.
2. Compounds according to claim 1 of the formula
3. Compounds according to claim 1 of the formula
4. Compounds according to claim 1 of the formula
5. (2Z,4E,6E,8E)-(R)-9-(4-Hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid.
6. Ethyl (2Z,4E,6E,8E)-(R)-9-(4-hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoate.
7. (2Z,4E,6E,8E)-(S)-9-(4-Hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid.
8. Compounds according to claim 1 of the formula
9. Compounds according to claim 1 of the formula
10. (2Z,4E,6E,8E)-9-(5-Hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid.
11. Compounds according to claim 1 of the formula
12. (2Z,4E,6E,8E)-9-(5-Oxo-2,6,6-trimethyl-cyclohexa-1,3-dienyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid.
13. (2Z,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-5-oxo-cyclohex-1-enyl)-nona-2,4,6,8-tetraenoic acid.
14. Compounds according to claim 1 of the formula
15. (2Z,4E,6E)-(R)-9-(4-Hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6-trien-8-ynoic acid.
16. The compounds of claims 1-15 for use as medicaments, especially for use in acne, psoriasis, light- and age-damaged skin as well as malignant and pre-malignant epithelial lesions.
17. Pharmaceutical preparations containing a compound of claims 1-15 and conventional pharmaceutical carrier materials.
18. Use of compounds of claims 1-15 for the production of medicaments for the therapy and prophylaxis of acne, psoriasis, light- and age-damaged skin as well as malignant and pre-malignant epithelial lesions.
19. A process for the manufacture of the compounds of general formula I and pharmaceutically usable salts thereof, characterized by reacting a compound of the general formula    wherein A is phenyl or substituted phenyl and Y^- is an anion, and X and the dotted bonds have the significance given above, with 5-hydroxy-4-methyl-5H-furan-2-one in the presence of a base, isomerizing isomers present in the reaction product in which the C=C double bond formed in the reaction has the cis configuration to the trans isomers and, if desired, subjecting the reaction product of formula I to one or more of the following operations:

    a) esterification of a carboxyl or hydroxy group;

    b) etherification of a hydroxy group;

    c) oxidation of a hydroxy group to the oxo group;

    d) reduction of an oxo group to the hydroxy group;

    e) steric inversion of a hydroxy group; and

    f) conversion of a carbon group into a salt.